Liver failure occurs in a number of acute and chronic clinical conditions, including drug-induced hepatotoxicity, viral infections, vascular injury, autoimmune disease, or blunts trauma. In addition, patients subject to inborn errors of metabolism may be at risk for developing liver failure. Symptoms of liver failure occurring as a result of these clinical conditions include, for example, fulminant acute hepatitis, chronic hepatitis, or cirrhosis, and in many instances, the restoration of normal liver function is vital to the survival of patients. For example, cirrhosis is the seventh leading cause of death and the fourth disease related cause of death in people between the ages of 25 to 44. (Source: American Liver Foundation).
In acute liver disease, the liver is able to regenerate after being injured. If the disease progresses beyond the liver's capacity to regenerate new cells, the body's entire metabolism is severely affected. Loss of liver function may result in metabolic instability combined with disruption of essential bodily functions (i.e., energy supply, acid-base balance and thermoregulation.) If not rapidly reversed, complications such as uncontrolled bleeding and sepsis occur, and dependent organs such as the brain and kidneys cease to function because of toxic by-products or because the liver is no longer synthesizing important nutrients. After large liver damage, liver tissue looses its regenerative and metabolic functions, and liver transplantation is a therapeutic strategy commonly used. However, the clinical application of liver transplantation is limited by the availability of human hepatocytes, liver tissue and the number of liver cells that can be transplanted safely at one time. Moreover, latence before surgery and post-surgery complications could be critical to counteract the acute phase of liver failure. Another therapeutic strategy consists in a liver resection (removal of a portion of the liver). The most typical indications for liver resection are a malignant tumor, a hepatocellular carcinoma or a proliferative biliary diseases including cholangiocarcinoma. Tumors can be primary (developed in the liver) or metastatic (developed in another organ, then migrated to the liver). The majority of liver metastases come from the colon. The single tumor or more than one tumor confined to either left or right side of the liver can be successfully resected with 5-year survival as high as 60%. Liver resections performed on patients with extrahepatic disease may relieve the symptoms caused by the tumor, but offer little improvement in survival. Benign tumors of the liver (adenoma, and focal nodular hyperplasia) can be successfully managed by liver resection as well. Liver resections are also performed on people willing to donate part of their liver.
Taking into account the importance of liver transplantation and liver resection, Several strategies have been suggested to stimulate liver regeneration and suppress or limiting liver failure in the case of liver resection or transplantation.
Liver cell is believed to be controlled by various growth stimulatory and growth inhibitory cytokines of autocrine or paracrine origin, however, the exact role and action mechanism of these growth factors is far from entirely understood. Cytokines are secreted peptides or proteins that regulate the intermediary metabolism of amino acid, proteins, carbohydrates, lipids and minerals. Cytokines include peptides or proteins that act to mediate inflammation and are involved in intracellular communication modulating cell proliferation, and adhesion of inflammatory cells to the walls of the vessels, and to the extra cellular matrix. Cytokines are essential for the communication between the liver and extrahepatic sites and within the liver itself. Cytokines interact with hormones such as glucocorticoids, resulting in a complex network of mutual control. Many cytokines exert growth activity in addition to their specific proinflammatory effects. The liver is an important site of cytokine synthesis and the major clearance organ for several cytokines. In liver disease, cytokines are involved in the onset of intrahepatic immune responses, in liver regeneration, and in the fibrotic and cirrhotic transformation of the liver.
Liver cell is also believed to be controlled by various growth factors. Growth factors are required to regulate developmental events or required to regulate expression of genes encoding other secreted proteins that may participate in intracellular communication and coordination of development and includes, insulin-like growth factor-I and II (IGF I and II), epidermal growth factor (EGF), type a and type b transforming growth factor (TGF-α and TGF-β), platelet-derived growth factor (PDGF).
In vitro, DNA synthesis in isolated hepatocytes has been shown to be stimulated by growth factors such as TGFα, or EGF. A further protein, named hepatocyte growth factor (HGF) has been shown to be a mitogen for primary hepatocytes.
Based on these observations, it has been proposed that these factors may be important mediator of liver regeneration. Consequently, growth factors as TGFα, EGF or HGF with growth factor-like activities have been indicated in the treatment of liver regeneration. However, these therapeutic strategies, suggested to stimulate liver regeneration and suppress liver failure, have not proved their efficacity without toxicity, and adverse effects. Namely, these growth factor favor tumor progression (Gang-Hong, et al., 1992; Lee 1992; Horiguchi, et al. 2002).
Consequently, there remains a need in the art for an effective method which would stimulate liver regeneration, would protect against liver failure, and would be deprived of adverse toxic and tumorigenic effects. This need exists in any patient population in which liver damage has been induced. This need exists not only for transplanted patients but also for donors, and patients having undergone a liver resection. Further, there is still a need in the art for novel therapeutically useful compounds, which stimulate liver regeneration.
Additionally, taking into account the poor availability of donor organs, living donor partial liver transplantation is recognized as a measure for overcoming the lack of organs, and facilities for partial liver transplantation. However, partial liver transplantation cannot be considered as a safe operation for adults representing the majority of transplantation patients because the resectable liver weight of donors is often less than the necessary liver weight for recipients. Thus there is a need for a mean for safe and rapid liver regeneration for small grafts.
Accordingly, it is an object of the present invention to provide a mean for the stimulation of liver regeneration after partial resection. An object of the present invention is also to provide a drug that can promote liver regeneration or hepatocyte growth after liver transplantation such as partial liver transplantation, and also after the occurrence of a discare causing liver failure, such as cirrhosis, acute hepatitis and chronic hepatitis.
These and further objects will be apparent to one ordinary skill in the art.